The long range objective of the proposed research is to advance the science of hemorheology in the realm of the microcirculation. The specific aims fall into five major areas: (i) to study the effect of particular chemical/physical perturbations on red cell deformability; (ii) to define the mechanisms underlying the loss of red cell deformability observed with intraerythrocytic parasites; (iii) to test the hypotheses that impaired red cell deformability in vivo (a) can induce increased capillary permeability and (b) leads to red cell sequestration in the spleen and other organs; (iv) to define the sensitivity of the rheoscopic methodology to clinically significant degrees of deformability impairment and to develop unambiguous links between indices of deformability observable in the rheoscope and the intrinsic material properties which govern red cell deformability; to study mechanisms of shear-induced platelet alterations, particularly under conditions of pulsatile flow. In the longer term the applicability of the rheoscope to the study of white cell rheology will be tested. The methodology of the planned interdisciplinary effort is predominantly experimental: In vitro studies of red cell deformability will rely on the rheoscope technique and filtrometry. These will be complemented by physical and chemical assays of membrane ultrastructure and by mathematical modeling of red cell tank-treading under shear. Platelets will be subjected to pulsatile shear in a cone-plate viscometer and their response determined by chemical assays post shear; their interactions with a collagen-coated glass surface under shear will be studied in the rheoscope. This research is expected to improve understanding of the impact of impaired red cell deformability on vascular pathophysiology. The proposed studies of shear-induced platelet alterations are pertinent to thrombotic and thromboembolic events in the natural circulation and in the presence of blood-processing artificial organs and vascular prostheses.